Lomitapide chemically known as N-(2,2,2-trifluoroethyl)-9-[4-[4-[[[4′(trifluoromethyl)[1,1′-biphenyl]-2-yl]carbonyl]amino]-1-piperidinyl]butyl]-9H-fluorene-9-carboxamide having the following structure designated as Formula 1.

Lomitapide is marketed as its mesylate salt under the trade name Juxtapid® as capsule; oral having dosage strengths Eq 5 MG Base, Eq 10 MG Base and EQ 20 MG Base, which inhibits the microsomal triglyceride transfer protein (MTP or MTTP) which is necessary for very low-density lipoprotein (VLDL) assembly and secretion in the liver.
Lomitapide and its pharmaceutically acceptable salts were disclosed in U.S. Pat. No. 5,712,279 A. This patent also discloses the preparation of Lomitapide by two different methods, which are shown below:

The process for the preparation of 9-(4-Bromobutyl)-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide of Formula II, comprises reacting 9-Fluorene carboxylic acid of Formula IV with 1,4-Dibromobutane in presence of n-BuLi in tetrahydrofuran, then chlorination with oxalyl chloride to form acid chloride compound as a crude oil, followed by amidation with 2,2,2-trifluoroethylamine hydrochloride in presence of triethylamine to yield 9-(4-Bromobutyl)-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide of Formula II.
The process for the preparation of piperidinyl biphenyl carboxamide derivative of Formula IIIa, comprises by reacting 4′-(trifluoromethyl)-2-biphenyl carboxylic acid of Formula VIII with oxalyl chloride in methylene chloride and dimethyl formamide, thereafter condensed with 4-amino-1-benzylpiperidine of Formula IX in presence of triethylamine in methylene chloride to yield N-(1-benzylpiperidin-4-yl)-4′-(trifluoromethyl)-[1,1′-biphenyl]-2-carboxamide of Formula X, which is deprotected using palladium/carbon in methanol and cyclohexane.
Lomitapide has been prepared by condensing bromobutyl 9H-fluorene carboxamide derivative of Formula II with piperidinyl biphenyl carboxamide derivative of formula Ma in dimethylformamide or by condensing bromobutyl 9H-fluorene carboxamide derivative of Formula II with 4-tert-Boc-amino piperidine to give 9-(4-(4-aminopiperidin-yl)butyl)-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide and thereafter condensed with 4′-(trifluoromethyl)-2-biphenyl carboxylic acid in the presence of triethylamine.
Lomitapide hydrochloride salt has been prepared by purifying Lomitapide free base by Column Chromatography (SiO2, MeOH: MeCl2) and thereafter reacting with etheral HCl in Methanol.
The present inventors have found that the prior-art process is not suitable commercially or on industrial scale as the process yields Lomitapide having dimer impurities, shown below designated as Formula A and Formula B.

Further the process involves purification using column chromatography, which is not suitable in the commercial scale production.
Further, the process shown for the intermediate preparation yields the intermediate compound having less purity and low yields, as the reaction doesn't go complete.
Further, the present inventors has also observed that the Lomitapide prepared by the prior-art process yields Lomitapide having the purity of ≤85% (by HPLC), which needs further purifications and hence the process is not suitable economically.
U.S. Pat. No. 5,760,246 A discloses the synthesis of 9-(4-bromobutyl)-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide of Formula II, which is as shown below:

Alkylation of N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide has been carried out by protecting alkane in presence of a base, wherein protecting group is selected from the group consisting of t-Bu(CH3)2Si or t-Bu(Ph)2Si, followed by deprotection and bromination. The present inventors have repeated the process and found that the obtained intermediate compound has less purity, low yields, commercially not feasible and economically not cost effective.
In view of the above, there is a need for the improved, cost-effective, industrially applicable process for the preparation of Lomitapide or its pharmaceutically acceptable salt thereof as well as its intermediates having high yield, purity as well as acceptable levels of impurities.